Magnetically responsive, biologically active substance and associated methods and apparatus

ABSTRACT

A biologically active substance is incorporated in a unitary body with a magnetically responsive material for carrying out diffusion testing. These may be, microbiological, immunological, serological and other biochemical examinations. The body is applied against a substrate or medium by application of an external magnetic field and a reaction region is produced at the site of the body and is measured by means of a reader.

CROSS RELATED APPLICATION:

This Application is a continuation-in-part of application Ser. No.156,738 filed June 25, 1971 now U.S. Pat. No. 3,843,450 which in turn isa continuation-in-part of Application Serial No. 705,539 filed February14, 1968 and now abandoned.

BACKGROUND OF THE INVENTION

a. Field of the Invention

The invention relates to diffusion testing in which the result isindicated by a change in growth and/or other reaction. Such testingincludes tests which may be biological (i.e. microbiological,immunological, serological and other biochemical tests inclusive ofclinical chemical tests) or chemical as long as they are suitable fordiffusion testing.

B. Description of the Prior Art

Microbiological and immunological tests are often carried out bydepositing an article for testing sensitivity, usually in the form ofpaper discs, tablets, or similar bodies, containing biologically activesubstances upon the surface of a solid or semi-solid substrate ormedium. In the case of microbiological testing, the biologically activesubstance reacts with a culture of a microorganism inoculated on or inthe substrate or with various substances in the substrate produced bythe microorganism, whereas for immunological testing the activesubstance reacts with various substances e.g. a serum added to thesubstrate or with various substances produced by a microorganism.

The substances deposited are diffused downwardly into the solid orsemi-solid substrate to react with the aforementioned agents in thesubstrate, i.e., the microorganism or substance produced by themicroorganism in the case of microbiological testing, and the addedsubstance or substance produced by a microorganism in the case ofimmunological testing.

A common test of this type is the determination of sensitivity ofmicroorganisms, e.g. bacteria, to biologically active substances, e.g.antibiotics, chemotherapuetics, etc. These experiments are frequentlycarried out by inoculating the substrate with the bacterial culture tobe determined. Then the biologically active substance, i.e. anantibiotic contained in an article in the form of a paper disc ortablet, is deposited on the substrate, either manually or mechanically,and then pressed lightly into contact with the substrate with a sterileneedle, tweezers or the like. The disc or tablet is absorbent and thesolid and semi-solid substrate contains aqueous medium which is absorbedin the disc or tablet whereupon the antibiotic is dissolved and diffusesinto the substrate. The substrate is then placed in an incubator and,after sufficient time, the effect of the antibiotic is noted bymeasuring the diameter of the circular zone of inhibition of the growth(i.e. region of sensitivity) surrounding the article. Mention shouldalso be made of the use of biologically active substances whichstimulate or enhance growth, i.e. of growth factors and growthrequirements, such as vitamins, amino acids, peptides, proteins,carbohydrates and minerals.

Various other examinations which involve diffusion and change in growthand/or other reaction in a solid or semi-solid substrate e.g. radialimmunodiffusion, can also be performed by the above method.Additionally, since diffusable agents from the substrate contained inthe aqueous medium will diffuse into the article, it is also possible toperform examinations which involve reaction in the article.

In order to compare the test results of bacterial sensitivity to variousantibiotics, or the other biologically active substances, it isessential that uniform and good contact between the article containingthe biologically active substance and the substrate is obtained. It isalso important to achieve as uniformly adjusted contact as possible fromone sensitivity test to the next in order to compare the results andestablish a basis for reliability.

A frequent source of error in determining sensitivity occurs when thearticle containing the biologically active substance is deposited orplaced askew on the substrate. Because of incomplete contact between thearticle containing biologically active substance and the substrate,diffusion into the substrate will be impaired sincne the amount ofdiffusion is a function of the contact area. Good contact results whenthe intended contact surfaces are in substantially complete and uniformcontact thus resulting in suitable and reproducible amounts ofdiffusion.

If uniformly good contact between the article containing thebiologically active substance and the substrate containing themicroorganism is not achieved, diffusion of the biologically activesubstance into the substrate will not be uniform and consequently astandard diffusion test procedure cannot be developed, since diffusionis highly dependent on the size of the contact area. The results ofsensitivity tests determined to a large extent how patients withinfectious diseases shall be treated.

Heretofore, it was impossible manually to achieve a uniformly goodcontact between biologically active substance and thebacteria-containing substrate or medium from one sensitivity test to thenext. Since laboratory technicians vary in manual dexterity,proficiency, and work experience, it is not surprising that uniformlygood contact cannot be achieved from one sensitivity test to another.Even greater variations in results can be expected between differentlaboratory technicians.

Although many attempts were made to overcome the foregoing and otherdifficulties none, as far as I am aware, was entirely successful whencarried into practice commercially on an industrial scale.

SUMMARY OF THE INVENTION:

An object of the invention is to provide an article containing an activeconstituent suitable for testing various reactions i.e. changes ingrowth and/or other reactions with an agent in a substrate by diffusionof the active constituent in the article into said substrate, or bydiffusion of the agent contained in the substrate into the article.

Another object of the invention is to provide a method and apparatus fortesting reactions using the above articles and substrates.

A further object of the invention is to make the method and apparatusoperative automatically under the control of an operator.

According to the invention, a magnetically responsive means isincorporated with the active constituent to form a unitary body whichcan be brought into contact with the substrate by application of anexternal magnetic force.

The active constituent may be an antibiotic for microbiologicalsensitivity testing, or for immunological testing it may be an antigenfor testing antibodies in the substrate or vice verse.

In general, the active constituent reacts with the agent of thesubstrate, either by diffusing into the substrate or by diffusion of theagent into the article containing the active constituent or by thecombination thereof.

The article comprises a wettable or absorbent carrier which carries theactive constituent and is inert thereto, said carrier beingsubstantially insoluble in the substrate.

In further accordance with the invention, the apparatus for testingreactions comprises a support for a substrate, dispenser means fordepositing a plurality of articles containing respective activeconstituents onto said substrate in spaced relation, said constituentsundergoing varying, i.e. different reaction with an agent in saidsubstrate and producing detectable results, index means for orientingthe dispenser means and said support relative to one another topredetermine the locations of said articles on the substrate, and readermeans correlated with said index means for determining said detectableresults at said predetermined locations.

It is further contemplated according to the invention that the articlesmay in some instances contain no active substance prior to use butincorporate only the magnetically responsive material. The articles areinitially porous and dry i.e. they are formed, for example, as paperdiscs and the active substance or test materials are added to the discseither before or after they are deposited on the substrate. Preferablythe active substance or test materials are in liquid form although it isalso feasible to utilize them in solid form such as powders.

BRIEF DESCRIPTION OF THE DRAWING:

FIG. 1 is a plan view showing tablets containing biologically activesubstances placed at random on a substrate with varying zones ofinhibition;

FIG. 2 is a plan view showing six different biologically activesubstances in respective carriers arranged in a predetermined pattern ona substrate;

FIG. 3 diagrammatically shows in perspective an apparatus for dispensingarticles containing active substances on a substrate in a petri dishprovided with a permanent magnet;

FIG. 4 shows several embodiments of carriers with active substances ofvarious shapes and incorporating magnetically responsive material;

FIG. 5 is a vertical section of one embodiment of a magnet system;

FIG. 6 is a vertical section of a dispenser with a different embodimentof a magnet system;

FIG. 7 is a schematic representation of a method of transmitting andstoring sensitivity test data;

FIG. 8 is an elevational view partly in section of a reading apparatus;

FIG. 9 is a top plan view thereof;

FIG. 10 is a simplified circuit diagram of a reading apparatus with aplurality of reading positions; and

FIG. 11 is a similar view of a reading apparatus in which each reactionzone is measured in succession with the same measuring device.

DETAILED DESCRIPTION

In carrying out this invention, a petri dish or other receptaclecontaining a solid or semi-solid substrate with a culture of a bacteriumor other microorganisms is associated with a means for establishing amagnetic field such as, for example, one or more permanent orelectromagnets attached to the bottom of the dish or incorporated in asupporting base for the petri dish. Thereafter an article containing abiologically active substance and a magnetically responsive material isplaced on the substrate and, through the action of magnetic force, formsa uniformly good contact with the substrate, thus avoiding the use ofmanual or mechanical pressure on the article to establish contact. Thepetri dish is placed in an incubator and the biologically activesubstance in contact with the substrate is then allowed a sufficientperiod in the incubator to produce growth and/or other reaction.Thereafter, a region or zone in which the biologically active substancehas inhibited, stimulated, or produced no change in bacteria growth isvisible to the eye. The measurement of this zone or region ofsensitivity results in an accurate measurement of the sensitivity of themicoorganism being tested to the particular biologically activesubstance.

The method of accurately measuring the sensitivity of a microorganism toa biologically active substance involves the steps of forming asubstrate containing a microorganism; placing an article containing abiologically active substance having incorporated therewith amagnetically responsive material on the substrate (or on a predeterminedposition of the substrate); causing a magnetic force to act on thearticle whereby the article is urged against the substrate and formsgood contact therewith; allowing sufficient time for the biologicallyactive substance to act on the microorganism; and thereafter measuringthe sensitivity region surrounding the article. The magnetic field neednot be applied until the article is deposited, although I prefer to havethe magnetic force acting on the article at the time of its release andprior to initial contact with the substrate so that the article will bedeposited in proper position on the substrate. After good contactbetween the article and the substrate is achieved, the magnetic forcemay be removed.

The articles may initially be blank and incorporate only themagnetically responsive material, and solutions of active substance canbe added to the articles either before or after the articles have beenpositioned on the substrate. This will be explained in greater detaillater.

This invention also provides an apparatus for testing the sensitivity ofa microorganism in which a receptacle suitable for holding a solidsubstrate (such, for example, as a petri dish) is provided with meansfor applying magnetic field to the substrate so that when an articlewhich comprises a biologically active substance, having incorporatedtherewith a magnetically responsive material, is placed on thesubstrate, the article is urged against the substrate and establishesgood contact therewith to permit accurate measurements of thesensitivity of the microorganism to the biologically active substance.

In addition, a mechanical dispensing means can be used for dispensingthe magnetically responsive articles with biologically active substancein random or predetermined positions on the substrate, the dispensingmeans being provided with a plurality of dispensing columns or tubularmembers. Also provided is an index means to provide orientation betweenthe dispensing means and the receptacle to enable the articles with thebiologically active substances to be deposited on the substrate inpredetermined positions. Such index means could, for instance, consistof register marks on the receptacle or its support base at predetermineddistances which correspond to similar marks on the dispensing apparatusat corresponding distances. The index means could also consist of adetent or locking means.

In conducting the sensitivity measurements, various mechanical readermeans are provided to facilitate actual measurements of the sensitivityregions surrounding the articles containing the biologically activesubstances. For example, an instrument provided with adjustableapertures arranged in a predetermined pattern corresponding to thedeposition points of the articles on the substrate can be brought intoalignment therewith by correlation with the index means, and therespective apertures adjusted to cover the sensitivity areas orrespectively adjusted to grade different degrees of positive reactionsor no reaction. The grading may be indicated by means of specialswitches or buttons. A mirror reflex instrument is also a satisfactorymeans for determining sensitivity. The general method of measuringsensitivity involves the measurements of the diameter of the sensitivityregion which is normally circular and surrounds the article containingthe biologically active substance.

Although the invention will be discussed chiefly in relation to thesensitivity of a microorganism to an antibiotic and vice versa, theinvention is broadly concerned with the use of articles associated withactive substances whose reactivity with an agent in a substrate isdetectable. Thus, for example, in immunological testing, the articlescontain an antigen to detect the presence in the substrate of anantibody or vice versa. Also, for example, it may be used forradio-immunodiffusion techniques and for fluorescent immunodiffusiontechniques. In general, any detectable reaction which occurs by means ofdiffusion of the active substances in the article into the substrate orof the agent in the substrate into the article is applicable to thepresent invention. The reaction may be detectable by the eye, by aspectrophotometer or by a radiation detector. The detectable changewhich may take place within the article itself, may for example, be atest for urease production by microorganisms by color change in thearticle.

As to the type of physical connection existing between an agent and asubstrate, various expressions have been used herein to indicate thisconnection. In this respect expressions have been used to refer to theagent being "in" the substrate, and correspondingly "on," "of,""contained in," "added to" and "associated with" the substrate. Inrespect to the invention, the essential point, whatever expression hasbeen used, is a physical association between the agent and thesubstrate. It will be understood that the various terms employed,broadly should be interpreted to express this fact.

In order for diffusion to be achieved, the article must be wettable orabsorbent to allow aqueous medium of the solid or semi-solid substrateto contact the active substances to provide for diffusion.

In the case of a carrier, such as a disc or a tablet for the activesubstance, the carrier should be substantially insoluble in thesubstrate to prevent any undesired influence on the diffusion processand the delicate reaction mechanism taking place, for example, byoccurrence of unspecific reaction. The wettability of the carrier isachieved by rendering it microporous in which case wetting is effectedby capillarity. In the case of paper discs, they, for example, may beabsorbent to the extent that they absorb approximately three times theirweight in distilled water. The active substance should desirably besubstantially uniformly distributed in the paper, and the paper shouldhave no interfering effect on the reaction. In the case of anantibiotic, the paper should have no interfering effect either onbacterial growth or on the action of the antibiotic. As an alternativeto conventional cellulose paper, various plastics satisfying the aboveconditions may be used as the inert carrier. Also suitable are glassfibre papers.

A dye may be incorporated in the article as coding means to indicate theparticular article to identify the reaction. The dye should besubstantially insoluble in aqueous medium and be inert to the reactione.g. have no interference with the antibiotic or the growth of themicroorganisms.

The articles may be supplied in a stack in a vacuum package.

Although the substrate might be a liquid, it preferably is a solid orsemi-solid which is microporous and possesses a high water content inorder to permit the diffusion mechanism to take place. The substrate mayinitially be dry and the water added thereto either directly or throughthe article itself. The substrate may be a gel such as a starch,gelatin, silica etc., or it may be a paper made on cellulose basis or aglass fibre paper. The most common gel is an agar gel which possessessubstantial strength even with very high water content. Agar is veryinert chemically and is suitable for examining diffusion tests. In caseof microbiological testing the substrate will contain a nutrient and itmust be sterile prior to inoculation. The substrate is placed on asupport which in the case of microbiological testing is generally apetri dish or large plate whereas in the case of immunological testingit may be a coated plate. Generally the substrate has a substantiallyuniform composition throughout its entire extent and is constituted ofone or more prescribed components in definite amount.

Referring now to the drawings, FIG. 1 depicts articles in the form oftablets containing various antibiotics placed at random on the surfaceof the substrate 1 in a petri dish 2 and surrounding the individualtablets 3 to 8 are sensitivity areas 9 shown with broken lines.

FIG. 2 shows six different antibiotic tablets 10 to 15 arranged in apredetermined pattern characterized by mutual equiangular distances andradii R from the center of the petri dish 16.

FIG. 3 shows an apparatus for utilizing this invention in which a base17 is made of a permanent magnet and on the base there is placed a petridish 18 containing a substrate 19 and six different antibiotic tablets10 to 15 placed thereon corresponding to those shown in FIG. 2. Thesetablets are placed in predetermined positions by a dispensing apparatus20 which consists of six tubular members 21 to 26, preferablyconstructed from nonmagnetic material, which at their lower ends areconnected to a housing 27 and at their upper ends are connected to asupporting plate 28. Each of the tubular members contains a stack ofarticles, the articles originally having been supplied in a vacuumpackage. In the housing 27, there are on each of the tubular members,depositing mechanisms of known construction which are familiar to thoseskilled in the art for releasing articles one at a time from each tubein one operation. The supporting plate 28 is suspended from an arm 29which in turn is adjustable suspended in a manner known to those skilledin the art in such a way that the dispensing apparatus 20 may be movedup and downn and can be swung from side to side in order to facilitate acorrect positioning of the dispensing apparatus 20 relative to the dish18. The dispensing apparatus can be brought into correct positionrelative to the petri dish with the register marks 30 and 31 on thepetri dish and base corresponding to the register marks 32 and 33 on thehousing 27. It is also possible to fix the dispensing apparatus and makethe petri dish movable. It is further possible to lock the petri dish onthe base and make either the dispensing apparatus or the assembly ofbase and petri dish movable. Instead of register marks, detents or otherreleasable locking means can be employed.

FIG. 4 depicts several embodiments of the article for testingsensitivity in accordance with this invention and which may be provided,for example, with a heavy magnetically responsive core as shown in FIG.4a. The core can be press fit into the article. Alternatively, themagnetically responsive material could be in the form of an annulusaround the article. FIGS. 4b and 4c depict the article in the form of aconical projectile to enable good contact with the substrate. FIG. 4dshows the tablet with anchoring devices which, for example, can be amagnetically responsive material such as iron, and which prevent thetablet from recoiling when deposited on the substrate. The paper discsand tablets may be impregnated or admixed with a magnetically responsivematerial as shown in FIG. 4e or the paper discs or tablets may beprovided with magnetically responsive components such as a foil attachedby adhesion as shown in FIG. 4f. In lieu of particles, the magneticallyresponsive material could be in the form of a grid or foil embedded inthe article. In order to prevent any interference of the magneticallyresponsive material with the reactants, an inert envelope may be appliedto the magnetically responsive material. In the case of the embodimentshown in FIG. 4a, the entire core is covered with a single inertenvelope, whereas in the embodiment in FIG. 4e, the individualmagnetically responsive particles may be coated prior to incorporationin the carrier.

FIG. 5 illustrates schematically a simple embodiment of magnet systemwhich can be used in the base of the apparatus when the depositionpoints on the substrate are disposed in a circle as in FIG. 2. Apermanent magnet comprised of the two axially magnetized Ticonal ringmagnets 35, one on top of the other, is affixed by means of an aluminumbolt 36 to a soft iron cup 37 which, together with a circular pole piece38 on the top of the magnet rings, encircles a circular air gap facingupwards, which, like the central bore of the magnet, is filled withnon-magnetic material, e.g. aluminum, as shown at spacers 39 and 40, togive the base a smooth upper surface. The air gap has a mean diameterequal to the diameter of the circle of positions (FIG. 2), which in turnis determined by the positions of the outlets of the dispenser, and thewidth of the air gap has to be adjusted to the height to the surface ofthe substrate, so that a substantial field component is able to act onthe articles on the substrate. With the substrates generally used, thisheight will normally be approximately 4-5 mm, and the width of the airgap should in that case be about the same.

Laboratory tests employing six different active substances asillustrated in FIG. 2, and with a device as shown in FIGS. 3 and 5 havebeen used and by way of example mention may be made of studies of theinhibiting effect of antibiotics in resistance determination, where, onan inoculated substrate consisting of, for example, a blood agar withouta peptone additive, are deposited paper discs containing such activesubstances as, for example:

Penicillin, sulphonamide, tetracyclin, erythromycin, methicillin,fucidin, streptomycin, nitrofurantoin, ampicillin, and nalidixin.

Articles can be used for other purposes than antibiotic sensitivitytesting, as previously mentioned, and by way of example the activesubstance in the article may be an antigen or an antibody forimmunological testing of an agent added to the substrate. Furthermore,the testing need not be biochemical, but may also be purely chemical,such as, determination of pH of the substrate within narrow limits byuse of articles containing respective chemical indicators undergoingchanges of color at different pH values.

It may also be mentioned that a number of active substances may besupported on a common carrier. In such case, the acitve substances maybe disposed in spaced pre-determined locations on the common carrierwith the magnetically responsive material either incorporated with theactive substances, as in the previously described embodiments, ormaintained separate therefrom in the spaces between adjacent substances.

FIG. 6 shows in greater detail another embodiment of magnet system and adispenser especially useful when discs in large numbers are to bedeposited. An aluminum base 41 is shown for centering and supporting adish 42 containing a substrate 43 and the base 41 contains a built-insystem of magnets consisting of horizontally magnetized permanentmagnets 44 which lie parallel to one another and are magnetizedalternately each in opposite directions and each of which is flanked bya pair of pole pieces 45 lying on edge which form air gaps 46 facingupwards at the upper surface of the base. Between each pair of magneticpoles there is a completely symmetrical flux field with the plane ofsymmetry in the middle of the air gap.

The dispenser 47 is supported by means of an arm 48 on an upright 49 onthe frame 41 for pivotal movement in a horizontal plane from theillustrated active position, which is determined by a stop, to aninactive position where the dish 42 can be inserted and removed. Theapparatus contains vertical dispensing tubes 50 adapted to hold stacksof discs 51 provided with magnetically responsive material, for example,in the form of an iron foil affixed by adhesion. The stacks of discsnormally rest on a baseplate 52, which is fitted with outlets 53laterally displaced in relation to the relevant dispensing tube 50. Thebottom disc in each stack is moved to the associated aperture by movinga pusher 55 against the bias of a return spring 56. In the caseillustrated, the pusher 55 is provided with a straight translationalguiding support which is preferred in dispensers with a plurality ofmagazines, as opposed to rotatable pushers, which are usually simplestwhen all the magazines are on a common circle.

The base 41 and the dispenser 47 can be aligned with one another suchthat the outlets 53 in the operating position are directly above the airgaps 46. Each set of discs released will thus fall parallel from theoutlets 53 in symmetrical magnetic fields and be positioned on thesubstrate 43 directly above the air gaps as shown at 51', and be drawninto uniform contact with the substrate.

Should it be desired to regulate the strength of the magnetic field,this may be effected by a pusher 57, which is supported for movementacross the magnets 44 at the bottom of the base 41 and the pusher isfitted with pieces of soft iron 58, which in the illustrated positionlie directly beneath successive pole pieces 45, but by displacement canbe caused to project more or less into the space between paired polepieces on the underside of the respective magnets and thus more or lessshunt the effective field. By being moved to a central positionunderneath the magnets, the pieces of soft iron 58 can be made almost toshort-circuit the magnetic fields, so that the effect on the upper sideis annuled if it should be so desired, to guard against any magneticaction on the discs while the dish is being removed. In order to removethe dish without annulment, it is lifted from the holder 41 directlyupwards a small distance, i.e. in the direction of the magnetic force soas not to disturb the position of the discs.

Among the sensitivity tests that can be undertaken with the apparatusillustrated in FIG. 5 with more than six deposition points, mention maybe made solely by way of example of determination of resistance to abacterium such as Escherichia coli of antibiotics such as penicillin,sulphonamide, streptomycin, chloramphenicol, tetracyclin, ampicillin,colistin, cephalosporin, nalidixin, nitrofurantoin, carbenicillin, andkanamycin.

The amount of magnetically responsive material in each article and thestrength of the field must, of course, be adapted to each other in thelight of the geometrical conditions, the orientation of the field, thepermeability of the components, etc., on the basis of the contactpressure desired. For a properly adjusted contact this will be theequivalent of the light manual pressure. With ordinary disc-shapedarticles of a diameter of approximately 6 mm, about 1 gram of force willgenerally be sufficient, and as an optional parameter 2 grams of forceproduces a surface pressure of about 1/10 g/mm².

The magnet system may also comprise small cup magnets placed under thepositions for the articles either in the substrate dish or, moresuitably, in a base on which it stands.

To bring about the desired effect without too strong a magnetic field,the magnetically responsive material in a standard paper disc shouldweigh slightly more than the rest of the disc, but occupy less volume,and the amount will be only a very small fraction of what would berequired to achieve the same contact pressure with the heaviness of anadded weight.

Experiments with the contact pressure achieved with a system of magnetsas shown in FIG. 6 have been performed with Ticonal magnets with an airgap of 5 mm, adjusted to provide a field intensity of approximately 650Gauss at a distance of 5 mm directly above the air gap, i.e. at a heightwhich should be quite sufficient to accommodate variations in the depthof the substrate and the thickness of the actual paper disc. Thevariations in field strength from block to block at this height werequite insignificant (± approx. 25 Gauss). For a circular iron foil witha diameter of approximately 5.5 mm and weighing approximately 20 mg, theheight above the air gap for magnetic forces respectively of 1 gram and2 grams were 9.5 and 6.5 mm respectively.

The experiment was repeated with an iron foil of the same diameter andweighing approx. 12 mg (0.06-0.07 mm thick), and here the heights were 8and 5 mm respectively.

Similar tests have also been carried out with more powerful (ceramic)parallel epipedic magnets of the Ferroxdure type, with which an air gapof 6 mm generated a field intensity of approximately 1250 Gauss of aheight of 5 mm, while approximately 650 Gauss was measured at a heightof 10 mm. The heights for generated forces of respectively 1 and 2 gramswere in the case of the first foil 15.5 and 11 mm respectively and forthe second foil 13 and 8 mm respectively. Such a system of magnets willthus be unnecessarily powerful under normal circumstances where theamounts of iron as mentioned above are used in the articles, but may besuitable in the case of still smaller quantities of iron, or if an extrapressure is desired, e.g. on articles to be drawn into the substrate.

It is, of course, possible to replace the permanent magnets in theillustrated systems by electromagnets of similar dimensions which can beregulated or switched on and off electrically.

In the conventional manner of dispensing articles onto the substrate,they often tend to land in a somewhat oblique position on the surface.Even a slight oblique angle on landing has a disturbing effect on thepossibility of providing good and uniform contact in a predeterminedposition with respect to the substrate.

Not only does this apply to light articles, which for inherent reasons,need an addition of a slight external pressure to establish good contactwith the substrate, but also to comparatively heavy articles.

A solid or semi-solid substrate, such as an agar substrate is as a ruleslippery and often somewhat elastic in its consistency. Particularly,when heavy articles are concerned, the features mentioned, will producean undesired effect on the capability establishing adequate contact inpredetermined positions with the substrate. Thus, deposition on thesubstrate by dropping articles from a dispenser, will, especially whenheavy articles are concerned, often produce a slight, althoughnoticeable, and disturbing rebound effect. This is due to the somewhatelastic consistency of the substrate mentioned. Furthermore, the kineticenergy of the heavy articles effected by the rebound from the substrate,especially in combination with the tendency of the articles to make askew landing, and, with the slippery substrate, has a detrimental effectwith respect to adequate positioning. The articles will more or lesstend to slide out of the desired location, without establishing good anduniform contact.

The invention makes it possible to avoid the obstacles disclosed above.Thus, by means of magnetic forces it is possible, according to theinvention, to deposit articles on the substrate in good and uniformcontact therewith at desired predetermined positions.

Furthermore, if magnetically responsive material, for example, iron,added to an article, amounts to such a degree that the article becomesheavy, it is possible, according to the invention, to use a relativelyweak magnetic field so as to create a weak magnetic force able toovercome the rebound and sliding effect produced during the initialcontact between the article and substrate during deposition. A strongmagnetic field may under these circumstances, using an articleincorporating a relatively substantial amount of magnetically responsivematerial, create a magnetic force so strong that on being added to theforce of pressure created by the heaviness of the article, results in anover-all pressure which may damage the supporting strength or structureof the substrate.

Articles may become heavy not only due to the added weight of themagnetically responsive material itself, but also to a combination ofthe magnetically responsive material, for example, iron, and othermaterials, for example, lead. The strength of the magnetic field to beused according to the invention, has to be adapted to the amount of ironor other magnetically responsive material present, on the basis of theinitial contact pressure desired.

An askew landing of a heavy article on the substrate will seriouslyinteract with the rebound and sliding effects, thereby seriouslydisturbing the possibility of positioning the article in good anduniform contact with the substrate in a predetermined position.According to the invention, it is possible by magnetic means to guidethe article in a balanced position or equilibrium during the flight,thereby avoiding the interactions mentioned.

In this connection it should be recalled that according to theinvention, it is possible by means of magnetic forces to eliminate thedisturbing effects of rebound, sliding and askew landing of an articlebeing dropped onto a substrate. As disclosed above, heavy articles areparticularly liable to create rebound and sliding effects by the initialcontact with a substrate.

It should be recalled that articles have been disclosed for providinggood contact with deeper layers of the substrate, for example, articlesin the form of conical projectiles. Such articles may also be in theform of balls. Also these articles may be made heavy by added weight,for example, by addition of a substantial amount of magneticallyresponsive material, for example, iron. They may also be subjected to arebound effect from the substrate in response to the initial contact asa result of the dropping. Also in this case, it will be possible bymeans of magnetic forces according to the invention to eliminate therebound and sliding effects by adapting the strength of the magneticfield to the amount of magnetically responsive material present, on thebasis of the initial contact pressure desired.

The magnetically responsive material added to the article may besupported and carried by a carrier of the article.

The invention is highly suitable also for prediffusion techniques i.e.pretreated substrates which are at present used by only a fewlaboratories. In the method currently employed with these techniques,antibiotic bodies are placed by hand or by means of a dispenser on thesubstrate before inoculation is carried out. They are then lightlypressed by the hand into contact with the surface of the substrate.After a suitable diffusion time, the bodies are manually removed, andinoculation performed. This technique suffers from a certaindisadvantage that the risk of contamination is considerable owing to thelarge amount of manipulation required. Furthermore, the identityreadings of the reactions are made difficult and uncertain since thearticles have been removed from the reaction sites before the readingstake place.

The invention makes it possible by means of magnetic forces not only todeposit the bodies on the surface of the substrate, but also to removethem. This can be done, for example, by turning the substrate dishupside down and removing the bodies by means of the magnetic forcegenerated by the magnet means in the base, the bodies being collected onpaper, or other material. The identity of the reaction can bemechanically determined by their correlated positions with respect tothe register marks 30, 31 which were employed as an index means for theposition of the dispensing apparatus relative to the dish and base.

The articles may, in some instances, contain no active substances priorto use, and these blank articles, according to the invention,incorporate magnetically responsive material.

For testing or assaying purposes, solutions of active substances or testmaterials prospective of containing active substances, will be depositedby the laboratory workers into the articles, for example, paper discs.

It is possible for the active substances or test materials prospectiveof containing active substances to be in solid form, for example, apowder. In this case liquid substrate will diffuse into the article anddissolve the solid test material resting on the top of the wettablecarrier, whereafter the test material will diffuse via the carrier intothe substrate.

The addition of active substances or test materials prospective ofcontaining active substances may be made either after the articles havebeen positioned on the substrate, or before. In the latter case, whenthe additive is a liquid, the articles may be dried before they arepositioned.

Positioning of the articles is carried out according to the invention,i.e. by magnetic means in order to provide a good and uniform contactwith the substrate. Dispenser means comprising index means, and aligningprocedures according to the invention are used in order to position thearticles in predetermined spaced positions as a prerequisite to usingthe reader means of the invention.

The use of primarily blank articles incorporating magneticallyresponsive material will be very useful for an assay technique andthereby for the search for and exploration of new active substances forthe purpose of manufacturing. The procedure is applicable to improvementof manufacture and to control of products.

The use of primarily blank articles is also useful for carrying outassay techniques in diagnostic laboratories, for example, for thepurpose of determining whether or not an active substance, for example,an antibiotic, is present in a tissue liquid, and if so, fordetermination of its level of concentration.

It is emphasized that the method of this invention is essentiallyequally applicable to regular diagnostic techniques as to assaytechniques. Thus, the method remains basically the same whether one istesting the activity of an agent to an active substance or whether oneis testing the activity of an active substance against an agent. Thedifference lies solely in the object of the tests, apart from thedistinction mentioned in those cases in which primarily blank articlesare used instead of articles primarily containing active substances.

The reactions and the reading of the results are essentially independentof whether articles primarily containing active substances or whetherblank articles to which active substances or test materials are added,are being used.

In connection with the exploration of potential vendible products andwith control examinations, it should be emphasized that the invention,as in diagnostic testing, in a very high degree will improve thereliability of the tests carried out by providing more reproducibleresults and avoiding errors.

Additionally, the increased speed and the reduced cost of labor providedby the method of invention, makes it possible to investigate a muchlarger number of potential vendible products and to carry out a greatlyincreased number of control tests.

The value of this is especially high, because of the fact that theevaluation of the results of tests, requires a considerable number ofreplicate tests in the various runs of investigation in order to producethe necessary statistical significance.

For this purpose the so-called large plate method advantageously may beused, because it is very suitable for carrying out laboratory diffusiontests in accordance with an assay design. Very suitable in thisconnection is the use of the embodiment of magnet system and dispensersystem shown in FIG. 6. Thus, the embodiment is especially useful, as inthe case of large plates, when articles in large numbers are to bedeposited, and the deposition points on the substrate are to be disposedin straight lines parallel to each other.

It will be understood, that in individual tests, the test components,i.e. the active substance and the agent, may prove to be inactive, inwhich case no reaction will occur, and the terms employed to refer tothe test components should be interpreted to include this possibility.

Furthermore, the test materials may or may not contain test components,i.e. active substance or an agent. For example, one may intentionallyuse a well-known active substance as a test component, or one may usetest materials prospective of containing active substances, such as whentest materials are dropped into blank articles with a view to findingout whether or not the materials contain active substances capable ofreacting with the agent present in the substrate, and if so,determination of their potencies or levels of concentration.

It is emphasized that an active substance or constituent added to anarticle for testing purposes, should be broadly interpreted to includeboth the intentional use of an active substance as well as thealternative use of a test material prospective of containing an activesubstance. Furthermore, it will be understood that a test materialprospective of containing an active substance may be any type of testmaterial suitable for assaying or analysis either pure or composite.

FIG. 7 is a schematic representation combining several features of theinvention in which 101 represents the depositing or positioning of thearticles containing biologically active substance on the substrate, 102represents the incubation period, 103 represents the sensitivityreading, which for example, may be taken with a mirror reflex unit inwhich the results in such a case go straight to the data processing unit104 and from there to various receivers 105, 106 and 107. When makingvisual readings of sensitivity, use is made of branch 103' with theresults being transmitted to data processing unit 104 and from there tothe various receivers 105, 106, and 107.

Another feature of this invention provides a system which achievesmechanization of primary noting (that is the direct reading andcompiling of sensitivity data) for suitable bacteriological examinationsand other suitable examinations, such as, for example, immunological orserological reactions taking into account the requirement for thepossibility of visual and personal control and supervision. Theinvention contemplates a method for determining change in growth orother reaction in a solid or semi-solid substrate in connection with theprimary noting of data and it is characterized in that the articlescontaining the substances bringing about the reaction are arranged onthe surface of the substrate in a pattern of predetermined positions sothat the sensitivity reactions, which can be read by a manually operatedinstrument having indicators arranged in oppositely disposed positions,can be checked visually while at the same time the indications may beread by machine, transmitted to a data processing unit where it can beassembled and coded, if necessary, and, thereafter, transmitted to areceiver where it can be stored for ultimate use and then subsequentlyread out when needed.

The identity of each reaction is determined by its position, a conditionwhich is machine sensitive in one operation not only for one reactionbut for the entire series of reactions in the pattern. It is alsopossible, in accordance with this invention, with the help of suitableapparatus, indicators, and the like, in a simple manner to indicate theresults of the reactions on the basis of the laboratory technician'sexperience. These indications are also of such a nature that they aremachine-sensitive and may be transmitted and stored.

The determination of the identity of the reaction and the indication ofthe result from visual observation may, according to the invention, beexpediently combined in the same apparatus.

Referring to FIGS. 8 and 9 therein is seen petri dish 18' placed in areading apparatus 60 for detecting the sizes of the zones of inhibition9 surrounding the articles 3-8. The base 61 of the reading apparatus maycontain electronic equipment for processing the measuring results. Inthe particular embodiment, it is assumed that the substrate and thebottom of the dish 18' are transparent and that the dish is centered ona glass plate 62 at the upper surface of the base 61 and illuminatedfrom below by light sources schematically indicated at 63. Correctangular positioning of the dish 18' on the base 61 is ensured bycorresponding register marks 64 on the dish and 65 on the base. Readingsare made visually through apertures in a holder 70 which is pivotablymounted in a horizontal plane about a column 71 on the base, so that itcan be swung aside to facilitate insertion and removal of the dish, theoperative position of which is determined by a stop 72. The position ofthe stop 72 is correlated with the register marks 64, 65 so that theapertures in holder 70 will be exactly above the articles 3-8. In theapertures of the holder 70 are fitted iris diaphragms 73, the aperturesof which can be adjusted by means of adjusting rings 74 which areaccessible on the upper side of the cover 75. On the holder 70, underthe cover, are means which sense the settings of the apertureselectrically and which, via flexible leads running through the hollowsupporting column, 71 are connected with electronic equipment in thebase 61.

The means for sensing the aperture setting may be, for example, voltagedividers as shown at 74' in FIG. 10. However, for the sake ofsimplicity, in this figure instead of iris diaphragms 73, slotdiaphragms 73' are shown having opposite indicator edges which can beadjusted independently of one another to opposite extremities of therespective reaction zones. One side of the indicator at all readingpoints is mechanically connected with the end of the voltage dividerwhich has a negative potential, while the other side is connected to thesliding contact of the voltage divider, so that the potential on eachsliding contact serves as a measure of the size of the relevant apertureand thus of the measured zone diameter. With an embodiment employingiris diaphragms as in FIGS. 8 and 9 it will be possible to use a similardevice with a fixed voltage-divider resistor on the holder and withsliding contacts on the adjusting rings of the diaphragms, by means ofwhich the diaphragms are adjusted to cover the relevant zones.

The measuring voltages from the sliding contacts thus constitute analogdata and are conducted via separate leads from the sliding contacts toan adapter 76. This may comprise, for example, an analog digitalconverter for conversion of the analog data to a binary code and may beprogrammed to coordinate individual measuring data with data relating tothe relevant active substances, these being identified by the individualleads for the respective positions. From the adapter, the data socoordinated can be delivered for registration either directly in acomputer or on a punched tape or similar medium, which each time isfirst provided with identification data and then with measuring data.Relaying from unit 76 can be done either in turn as and whenmeasurements are made, or at the end, after all the indicators have beenadjusted, as the leads from the sliding contacts can be connected tocontacts in a multiplexer which is released by pressing a button 77.

Should there be more reading positions than occupied positions, thesliding contacts in the unoccupied positions will be in the zeroposition; this will have no effect on the remaining readings. And if bychance a position should be missed in the reading process, the onlyconsequence will be that the measurement in question will be lost, asall the measurements made will remain alloted to their respective,correct identifications.

Although in FIG. 8 the articles containing the active substance aredeposited on the substrate during measurement, it makes no difference ifthe articles have been removed from the substrate before measurementsare made, as for example in prediffusion techniques, as measurement isonly undertaken on the formed zones. It will be recalled that inprediffusion techniques, inoculation of the substrate is performed afterthe articles have been in contact with the substrate for a certainperiod in which diffusion takes place and subsequently the articles areremoved.

FIG. 11 shows a simpler embodiment of reader apparatus, employing onlyone measuring instrument, in the form of a sliding gauge 78 similar to amicrometer. The substrate is illuminated by a light falling onto it sothat under normal circumstances it will not be necessary to provideillumination from below through the bottom of the dish. The dish ismounted on a base or turntable supported on a rotatable shaft 79. Theindicators of the gauge 78 are adjusted to the diameter of the reactionzone, which is indicated by a broken line at 4'. The gauge supports avoltage divider 74" fitted with a sliding contact 80 mechanicallyconnected to a movable indicator 81 of the gauge. The voltage on thesliding contact thus again constitutes a measure of the measured zonediameter d and is relayed to an adapter 76'. Voltage is also applied toa selector arm 82 which is insulated and mounted on the shaft 79 and inturn cooperates with fixed contacts placed at angular distancescorresponding to the various positions in the dish when this is properlyaligned at an index or measuring position. The fixed selector contactsare connected in turn via separate leads with the adapter 76'. Themeasuring instrument 78 is employed at the same location and the dish isrotated on a turntable to bring the measuring zones to the instrument.The instrument can be supported on a suitable radial guide.Alternatively, the instrument may be connected with the unit 76' byflexible connectors so as to be portable. The axle 79 of the turntableis turned to turn the dish, after each reading, through an anglecorresponding to the angular spacing between the measuring zones. Inthis case the registrations are performed successively, in other words,for example, by the set position and the set voltage being registeredcoordinately for each individual reading by pressing a button 77'.

Instead of using voltage dividers which cooperate with an analog digitalconverter in the adapter, it is, of course, also possible to use othercomponents for the purpose, e.g. to fit binary position encoders withdirect mechanical connection to the measuring instruments.

Finally, it is possible to use the apparatus as shown in the drawing notonly to measure diameters, but also to supply data for indicating theabsence or presence of a reaction or for grading positive reactions, byassigning to such observations specific settings of the measuringinstruments. This is applicable not only for diffusion testing but alsofor testing not involving diffusion such as, phage typing. In fact, itis applicable to various biochemical and chemical tests, such asclinical chemical tests; so-called spot tests; and immunofluorescenttechniques. Such biochemical tests may include, for example, colorchange in the article itself, e.g. in a test for urease production bymicroorganisms.

The identification of the reaction and indication of its result may befed into a central data unit as two machine sensitive functions. In thismanner, it has been possible to establish a primary noting by machine ofbacteriological or other data in machine contact with a central dataprocessing unit with the excellent advantages offered. Such advantages,are, for example, saving in recording, storing, communication andanalysis of the data.

In the first phase of data processing, the primary noting handles thebasic material on which the subsequent phases of the process build. Bymechanical means primary noting is much more reliable than manual means,and faster registration and flow is thus possible. During manual primarynoting of data, errors may easily arise, not the least of which occursin bacteriological and similar examinations (for instance, serologicalexaminations) in which the reading or collecting of data can bemonotonous. The reactions which are uniform and usually occur in largenumbers are, as a rule, only differentiated under the guidance ofmemory. As identifying marks, various colors or symbols on the tabletsor other articles containing biologically active substances which occurin the reactions are used, or the marks may be indicated by typicallaboratory markers (such as, for example, a grease pencil) on the bottomof the petri dish. When at the same time measurements have been made andnoted manually the possibility of error arises.

Errors such as these in primary noting are very difficult to discoverand correct. In consequence, errors are introduced in the basic materialwith all the complications which are later involved in furtherprocessing. Results may be interchanged, and thus faulty data iscompiled concerning what has been found in the patients. This, in turn,could lead to incorrect treatment. Incorrect measurements or notationcan also result in many other complications. Thus, errors in primarynotation can lead to complications in the detection of infectiousdiseases and the large group of epidemics caused by microbes. It isevident that by the use of the system in accordance with this inventionerrors of this nature are kept to a minimum and a high degree ofreliability can be placed on the data collected and stored through theelectronic data processing unit.

A central health registry system can be established in accordance withthis invention. The objective is to build up an intergratedcommunication system between various sectors of community healthservices. By way of example, it shall be possible when admitting apatient to the hospital to speedily and reliably collect informationfrom a central storage unit with respect to any earlier stays in thehospital or other examinations which may have been made. New findings ofpossible interest may similarly be at the disposal of the attendingphysician. It must be possible to provide cumulative transcriptionsconerning findings from patients. A correct basic material plays here,as elsewhere, a decisive role, the effect of which the invention will beable to realize with regard to the examinations made. Similarly theeffect of the information on the realization of a speedy flow will be ofvital significance, particularly in acute and dangerous cases.

In the bacteriological laboratory, it is, generally speaking, unusual tocarry out the work with a system in mind whereby a growth or a reactionis to be placed in a position or in a pattern. Normally, the inoculationof the material of the placing of the reactions occurs at random on thesurface of a substrate or in a tube containing a liquid substrate.

Viewed as a whole, the method of this invention for collecting,transmitting and storing laboratory information proceeds in distinctphases or steps.

In the first phase the agent is inoculated on or in the substrate, andas a rule the positioning of articles is carried out, the effects orreactions of which is to be tested. Such articles may includeantibiotics whose sensitivity to microbes is to be determined.

In the second phase incubation is carried out in order to develop thegrowth and/or other reaction. The container in which the inoculatedsubstrate lies is placed in an incubator usually at about 37°C. Itusually remains there 18 to 24 hours. Sometimes the period may beshorter, but it may also extend up to several weeks.

The conditions should desirably and substantially be under control. If,in a particular technique there is required a secondary application, as,for example, of an article containing another substance, this shoulddesirably be done also under controlled conditions, such as, control oftime at which it is applied, control of amount added and of the site atwhich the addition takes place.

In the third phase the results are read and their nature and extentrecorded.

Very wide-spread is, for example, the usage of antibiotics in the formof small, at least approximately, circular tablets, paper discs, andsimilar bodies containing the antibiotics. These are, in accordance withthis invention, guided by means of the magnetic attraction into thedesired position on the surface of an inoculated substrate in goodcontact with the substrate. After an incubation period the effects areautomatically read off under the control of the operator by measuringthe spread of area of sensitivity which is formed around the individualantibiotic bodies.

In contradistinction, the prior art requires manual procedures which areexacting and demanding, and above all, time consuming. This is becominga serious problem due to the increasing numbers of such tests inlaboratories. Such manual procedures as positioning the individualbodies requires skill and is laborious, while additionally, manualreading is cumbersome and time consuming and must be carfully made inorder to obviate erroneous readings which could have fatal consequencesas the treatment of the patient concerned is decided, on the basis ofsuch sensitivity determinations.

In accordance with the invention, this is avoided by automaticallylocating the bodies containing the antibiotics at specific predeterminedlocations and correlating the reading or measurement of the reactionzones at said predetermined locations whereby for each reading, twosignals are always produced, one for the magnitude of the reading, theother for the identification thereof.

Although the present invention has been described in conjunction withpreferred embodiments, it is to be understood that various modificationsand variations thereof will become apparent to those skilled in the artwithout departing from the spirit and scope of the invention as definedin the appended claims.

What is claimed is:
 1. An article for carrying out microbiological andsimilar biochemical examinations, said article comprising a test dose ofan antibiotic substance whose reactivity with microorganism of a mediumin which the test dose is brought into contact is the subject ofinvestigation, a dry and porous carrier which is free of said test doseand to which said test dose can be added, said carrier being inert tosaid antibiotic substance, and metallic magnetically responsive meansdisposed on and supported by said carrier and intact with the carrier asa unitary body for pressing the carrier into substantially uniformcontact with the medium under the action of an external magnetic fieldso that the test dose is brought into contact with said medium, saidmagnetically responsive means being dimensioned and proportionedrelative to said carrier to provide a pre-determined operative contactpressure between the carrier and the medium under the influence of theexternal magnetic field, the amount of magnetically responsive meansbeing only a very small fraction of that required to achieve the samesaid contact pressure by its added weight.
 2. An article as claimed inclaim 1 comprising an inert envelope on said magnetically responsivemeans to isolate the same from said antibiotic substance.
 3. An articlefor carrying out immunological and similar biochemical examinations,said article comprising a test dose of a substance selected from thegroup consisting of the class of antigens and the class of antibodies,the substance being active in an immunological examination of asubstituent from the other class associated with a medium with which thetest dose is contacted, a dry and porous carrier which is free of saidtest dose and inert thereto and to which said test dose can be added,and metallic magnetically responsive means disposed on said carrier forpressing the carrier into substantially uniform contact with said mediumunder the action of an external magnetic field so that the test dose isbrought into contact with said medium, said magnetically responsivemeans being dimensioned and proportioned relative to said carrier toprovide a pre-determined operative contact pressure between the carrierand the medium under the influence of the external magnetic field, theamount of magnetically responsive means being only a very small fractionof that required to achieve the same said contact pressure by its addedweight, said carrier and magnetically responsive means remaining intactas a unitary body after said immunological examination has beencompleted.
 4. An article as claimed in claim 3 comprising an inertenvelope on said magnetically responsive means to isolate the same fromsaid test dose.
 5. The combination comprising: an article for carryingout diffusion testing, said article comprising a test dose of an activesubstance which may react with an agent of a medium by diffusiontherewith, a dry and porous carrier which is free of said activesubstance and to which said test dose can be added for diffusion withsaid medium with the carrier in contact with the medium, and metallicmagnetically responsive means incorporated with said carrier as aunitary body; and means for applying a magnetic force to said metallicmagnetically responsive means to urge said carrier against said mediumso that the active substance can be brought into active association withsaid agent.
 6. The combination as claimed in claim 5 wherein said meansfor applying the magnetic force is disposed to apply said magnetic forcethrough said medium in a direction substantially perpendicular to thesurface of the medium.
 7. The combination as claimed in claim 5 whereinsaid active substance is a biologically active substance and saiddiffusion test is a biochemical examination.
 8. In combination fortesting purposes: a substrate having substantially uniform microporosityto permit diffusion to occur therein substantially equally in alldirections, an active constituent capable of being brought intooperative association with said substrate to undergo diffusion therewithuniformly in all directions, a dry and porous carrier which is free ofsaid active constituent and to which said active constituent can beadded for diffusion with said substrate, said substrate beingconstituted of prescribed components in definite amounts and includingan agent, uniformly distributed at least on the surface of thesubstrate, whose reactivity with said active constituent is to bedetermined by the production of a detectable result, said substratebeing inert to the active constituent, and metallic magneticallyresponsive means incorporated with said carrier as a unitary body andacting in combination therewith, under the action of an externalmagnetic field, for urging said carrier against said substrate with apre-determined contact pressure to allow the active constituent to bebrought into reactive association with said agent thereof for producingsaid detectable result such that the testing can be reliably reproduced.9. The combination as claimed in claim 8 wherein said substrate has asubstantially uniform composition throughout its entire extent.
 10. Anarticle for testing reaction with an agent associated with a substratewith which it is brought into contact, said article comprising a testdose of an active substance, the reactivity of the test dose with theagent of the substrate being the subject of examination, a dry andporous wettable carrier which is free of said test dose and to whichsaid test dose can be added, said carrier being inert with respect tosaid active substance and substantially insoluble in said substrate, andmetallic magnetically responsive means supported and carried by saidcarrier and intact with said carrier as a unitary body for urging thecarrier into substantially uniform contact with said substrate under theaction of an external magnetic field, said magnetically responsive meansbeing dimensioned and proportioned relative to said carrier to provide apre-determined operative contact pressure between the carrier and thesubstrate under the influence of the external magnetic field, the amountof magnetically responsive means being only a very small fraction ofthat required to achieve the same said contact pressure by its addedweight, said carrier and magnetically responsive means remaining intactafter the reaction has been completed.
 11. An article as claimed inclaim 10 wherein said carrier is microporous.
 12. An article as claimedin claim 10 wherein said active substance is an antibiotic, an antigenor an antibody.
 13. An article as claimed in claim 10 wherein saidcarrier is in the form of a tablet.
 14. An article as claimed in claim10 wherein said carrier is cone-shaped.
 15. An article as claimed inclaim 10 wherein said carrier is paper.
 16. An article as claimed inclaim 10 wherein said carrier is plastic.
 17. A method of measuring therelative sensitivity of a microorganism and a biologically activesubstance, which comprises forming a substrate containing themicroorganism; forming an article constituted as a unitary body havingincorporated therewith metallic magnetically responsive material;applying a magnetic force to said article in a direction substantiallyperpendicular to the surface of said substrate to urge the articleagainst the substrate and form good contact therewith, said articlebeing initially porous and dry and free of a biologically activesubstance, adding said biologically active substance to said article;allowing sufficient time for the biologically active substance to act onthe microorganism; and thereafter measuring a sensitivity regionsurrounding the article.
 18. A method as claimed in claim 17 whereinsaid biologically active substance is added to the article after depositthereof on the surface of the substrate.
 19. A method as claimed inclaim 17 wherein said biologically active substance is added to thearticle before deposit thereof on the surface of the substrate.
 20. Amethod of measuring the relative sensitivity of a microorganism,immunological agent or other similar biochemical agent with respect to abiologically active substance, said method comprising forming asubstrate containing said agent, providing an article adapted forcontaining the biologically active substance, incorporating metallicmagnetically responsive material with the article, applying an externalmagnetic force to the magnetically responsive material incorporated inthe article in a direction substantially perpendicular to the surface ofsaid substrate, said article initially being dry and porous and addingthe biologically active substance to said article such that with thearticle pressed against the substrate by the magnetic forcesubstantially uniform contact of the biologically active substance withsaid substrate will be provided, allowing sufficient time for thebiologically active substance to act on the agent, and thereaftermeasuring a reaction region around the article.
 21. A method as claimedin claim 20 wherein said biologically active substance is added to thearticle after deposit thereof on the surface of the substrate.
 22. Amethod as claimed in claim 20 wherein said biologically active substanceis added to the article before deposit thereof on the surface of thesubstrate.
 23. A method as claimed in claim 20 wherein said magneticfield is applied through the substrate.
 24. A method for testingreactions comprising forming a substrate of prescribed composition andincluding an agent, forming an article, incorporating metallicmagnetically responsive material in said article, applying an externalmagnetic force to said article in a direction substantiallyperpendicular to the surface of the substrate to press the articleagainst the substrate, then adding to said article active constituentwhose reactivity with the agent of the substrate is to be determined bythe production of a detectable result and determining said detectableresult.
 25. A method as claimed in claim 24 wherein said detectableresult is the production of a reaction region around said article, themeasurement of said result comprising measuring the size of saidreaction region.
 26. A method for testing reactions comprising forming asubstrate of prescribed composition and including an agent, depositing aplurality of articles individually on the substrate by dropping thearticles thereon, adding to each of said articles by separate deposit arespective active constituent whose reactivity with the agent of thesubstrate is to be determined by the production of a detectable result,indexing the deposit of the articles so that they occupy pre-determinedidentified locations on said substrate, detecting the detectable resultat each location of an article, producing a first electrical signal foreach article indicative of the magnitude of the result while indexingthe detecting of the results in correlation with the deposit of thearticles, producing a second electrical signal indication of theindentity of the article being examined so that first and second signalsare produced for each article, and correlating said electrical signalsso that each result which is detected is identified with the particulararticle.
 27. A method for testing reactions comprising forming asubstrate of prescribed composition and including an agent, forming aplurality of dry, porous articles, adding a respective activeconstituent to each article by separate deposit, the relative reactivityof the active constituent with the agent of the substrate being thesubject of investigation and being determinable by the production of adetectable result, depositing the articles individually on the substrateby dropping the articles thereon, indexing the deposit of the articlesso that they occupy pre-determined identified locations on saidsubstrate, detecting the detectable result at each location of anarticle, producing a first electrical signal for each article indicativeof the magnitude of the result while indexing the detecting of theresults in correlation with the deposit of the articles, producing asecond electrical signal indicative of the identity of the article beingexamined so that first and second signals are produced for each article,and correlating said electrical signals so that each result which isdetected is identified with the particular article.
 28. An article asclaimed in claim 1 wherein said test dose is in liquid form.
 29. Anarticle as claimed in claim 3 wherein said test dose is in liquid form.30. The combination as claimed in claim 5 wherein said test dose is inliquid form.
 31. The combination as claimed in claim 8 wherein saidactive constituent is in liquid form.
 32. An article as claimed in claim10 wherein said test dose is in liquid form.
 33. A method as claimed inclaim 17 wherein said biologically active substance is added to saidarticle in liquid form.
 34. A method as claimed in claim 20 wherein saidbiologically active substance is added to said article in liquid form.35. A method as claimed in claim 26 wherein said active constituent isseparately deposited on the articles in liquid form.
 36. A method asclaimed in claim 27 wherein said active constituent is separatelydeposited on the articles in liquid form.
 37. A method as claimed inclaim 24 wherein said active constituent is added to said article inliquid form.